Griffett Publishes Breakthrough Research on Fatty Liver Disease

Published on 03 November 2020

A recently published paper co-authored by Kristine Griffett, Ph.D., assistant professor of pharmacology at University of Health Sciences and Pharmacy in St. Louis, has shed light on the beneficial effects of REV-ERB nuclear receptor activation in the treatment of non-alcoholic steatohepatitis (NASH), a condition associated with progressive liver disease.

The paper, featured in PLOS One, a peer-reviewed open access scientific journal published by the Public Library of Science, highlights research conducted by Griffett and her research team consisting of Bahaa Elgendy, Ph.D., Ph.D., assistant professor of medicinal chemistry at the University, Tom Burris, Ph.D., FAAAS, FAHA, Alumni Chair in Pharmaceutical Education and vice president for research and graduate education at the University, and Gonzalo Bedia-Diaz, M.S., senior research technician in the Center for Clinical Pharmacology.

Through its work, the research team studied obese and diabetic mice models which developed NASH after being fed a diet featuring trans fats, fructose and cholesterol.

“NASH is the next phase of fatty liver disease,” explained Griffett. “In humans, the onset of NASH represents the point at which an individual sees fibrosis of the liver and hardening starts to occur, and severe fibrosis can be a gateway to cirrhosis. With no treatments for NASH currently available, this research project gave us the chance to study this type of severe liver disease and how it could be impacted by REV-ERB nuclear receptor activation.”

Nuclear receptors are transcription factors activated by ligands and involved in diverse biological processes, such as cell growth and differentiation and metabolism. Many diseases, including NASH, are directly or indirectly related to nuclear receptor signaling, and nuclear receptors serve as key modulators for the onset and progression of non-alcoholic fatty liver disease.

Specifically, REV-ERB nuclear receptors are transcriptional repressors that regulate a variety of physiological processes including inflammation, circadian regulation, muscle regeneration and lipogenesis, a process of fatty acid and triglyceride synthesis from glucose or other substrates which takes place predominantly in the liver.

Through their research, Griffett’s team focused on uncovering effects in NASH livers when REV-ERB is activated by the compound, SR9009, which has been reported to elicit a range of beneficial effects in healthy and diseased animal models and cell systems.

“We wanted to see if the SR9009 REV-ERB mechanism could suppress both inflammation and lipogenesis in these mouse models,” said Griffett. “By doing so, our hope was that we could alleviate the NASH phenotype. While we didn’t see an effect on lipogenesis, we were surprised to see a total reversal of fibrosis in the mice we studied. We’d never seen a reversal like this before, and there’s nothing currently out there clinically that can do that, so this was a really exciting discovery.”

Griffett says the study represents an important step forward as researchers work to design and develop more drug-like compounds specific for REV-ERB to target NASH and fibrosis.

“Our work opens up the idea that targeting REV-ERB in these models may be a really novel therapeutic option,” noted Griffett. “While the science isn’t yet clear on when or how fatty liver disease turns into NASH, we know that once it gets to that point, there’s currently no way to treat the disease. If our work can be a gateway to eventually helping patients in the later stages of fatty liver disease, that’s really exciting.”

View the full text of Griffett’s paper here.

For details about the exciting research projects happening at the University, visit uhsp.edu/research. To learn more about projects underway the Center for Clinical Pharmacology, visit clinicalpharmstl.org.

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